Naturally occurring somatostatins (SSTs), which are also known as somatotropin release-inhibiting factors (SRIFs), have diverse biological effects in many cells and organs throughout the body. They are produced by normal endocrine, gastrointestinal, immune and neuronal cells, as well as by certain tumors (Patel, Y. C., Frontiers in Neuroendocrinology, 20(3): 157-198 (1999); Froidevaux, et al., Biopolymers, 66(3): 161-83 (2002)). The effects of somatostatins are broadly inhibitory on the secretion of hormones, as well as on the proliferation and survival of cells. They inhibit both endocrine secretion (e.g., growth hormone, insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide and secretin) and exocrine secretion (e.g., gastric acid, intestinal fluid and pancreatic enzymes) (Patel, Y. C., (1999) op. cit.). Somatostatins also inhibit proliferation of both normal and tumor cells (Bousquet et al., Chemotherapy, 47(2): 30-39 (2001)).
These biological effects of somatostatins, all inhibitory in nature, are elicited through a series of G protein coupled receptors, of which five different subtypes have been characterized (SSTR1-5) (Reubi, et al., Cancer Res, 47: 551-558 (1987); Reisine, et al., Endocrine Review, 16: 427-442 (1995); Patel, Y. C., (1999) op. cit.)). SSTR1-5 have similar affinities for the endogenous somatostatin ligands but have differing distribution in various tissues.
Somatostatin analogs were initially developed for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating data has supported their role as antiproliferative agents, capable of stabilizing tumor growth in patients with metastatic neuroendocrine malignancies, including carcinoid and pancreatic endocrine tumors (Strosberg, et al., World J Gastroenterol, 26(24): 2963-2970 (2010)).
Examples of somatostatin analogs are disclosed in, e.g., PCT publication Nos. WO 02/10215; WO 2007/144492; WO 2010/037930; WO 99/22735; and WO 03/014158.
As is well known to those skilled in the art, SRIF and analogs thereof are useful in the treatment of a great variety of diseases and/or conditions. An exemplary but by no means exhaustive list of such diseases and/or conditions would include: Cushing's syndrome (Clark, R. V. et al., Clin. Res., 38: 943A (1990)); gonadotropinoma (Ambrosi, B. et al., Acta Endocr. (Copenh.), 122: 569-576 (1990)); hyperparathyroidism (Miller, D. et al., Canad. Med. Ass. J. 145:227-228 (1991)); Paget's disease (Palmieri, G. M. A. et al., J. of Bone and Mineral Research, 7: 5240 (1992)); VIPoma (Koberstein, B. et al., Gastroenterology 28: 295-301 (1990); Christensen, C., Acta Chir. Scand., 155: 541-543 (1989)); nesidioblastosis and hyperinsulinism (Laron, Z., Israel J. Med. ScL, 26: 1-2 (1990)); Wilson, D. C. et al., Med. Sci., 158: 31-32 (1989)); gastrinoma (Bauer, F. E. et al., Europ. J. Pharmacol., 183: 55 (1990)); Zollinger-Ellison syndrome (Mozell, E. et al., Surg. Gynec. Obstet., 170: 476-484 (1990)); hypersecretory diarrhea related to AIDS and other conditions (Cello, J. P. et al., Gastroenterology, 98: A163 (1990)); elevated gastrin-releasing peptide levels (Alhindawi, R. et al., Can. J Surg., 33: 139-142 (1990)); diarrhea associated with chemotherapy (Petrelli, N. et al., Proc. Amer. Soc. Clin. Oncol., 10: 138 (1991)); irritable bowel syndrome (O'Donnell, L. J. D. et al., Aliment. Pharmacol. Therap., 4: 177-181 (1990)); pancreatitis (Tulassay, Z. et al., Gastroenterology, 98:A238 (1990)); Crohn's disease (Fedorak, R. N. et al., Can. J. Gastroenterology, 3:53-57, 1989)); systemic sclerosis (Soudah, H. et al., Gastroenterology, 98:A129 (1990)); thyroid cancer (Modigliani, E. et al., Ann. Endocr., 50: 483-488 (1989); psoriasis (Camisa, C. et al., Cleveland Clinic J. Med., 57:71-76 (1990)); hypotension (Hoeldtke, R. D. et al., Arch. Phys. Med. Rehabil, 69: 895-898 (1988); Kooner, J. S. et al., Brit. J. Clin. Pharmacol. 28: 735-736 (1989)); panic attacks (Abelson, J. L. et al., Clin. Psychopharmacol. 10: 128-132 (1990)); sclerodoma (Soudah, H. et al., Clin. Res., Vol. 39, p. 303A (1991)); small bowel obstruction (Nott, D. M. et al., Brit. J. Surg., 77:A691 (1990)); gastroesophageal reflux (Branch, M. S. et al., Gastroenterology, 100: A425 (1991)); duodenogastric reflux (Hasler, W. et al., Gastroenterology, 100: A448(1991)); Graves' disease (Chang, T. C. et al., Brit. Med. J., 304: 158 (1992); polycystic ovary disease (Prelevic, G. M. et al., Metabolism Clinical and Experimental, 41: 76-79 (1992); upper gastrointestinal bleeding (Jenkins, S. A. et al., Gut. 33:404-407 (1992)); Arrigoni, A. et al., American Journal of Gastroenterology, 87: 1311 (1992)); pancreatic pseudocysts and ascites (Hartley, J. E. et al., J. Roy. Soc. Med., 85:107-108 (1992)); leukemia (Santini et al., 78:429A (1991)); meningioma (Koper, J. W. et al., J. Clin. Endocr. Metab., 74:543-547 (1992)); and cancer cachexia (Bartlett, D. L. et al., Surg. Forum., 42:14-16 (1991)).
Additionally, various studies have demonstrated the inhibitory effects of somatostatin and analogs thereof in patients with acromegaly; endocrine pancreatic tumors, such as insulinomas and glucagonomas; ectopic tumors, such as gastrinomas; and vasoactive intestinal peptide (VIP)-producing tumors. Schally A V, Front Neuroendocrinol., 22: 248-91 (2001); Schally A. V., Cancer Res., 48:6977-85 (1988).
In view of the foregoing, clearly needs remain for additional somatostatin analogs for use in the inhibition, prevention, and/or treatment of disease.